Synthesis of pH responsive carriers for pulmonary drug delivery of anti-tuberculosis therapeutics: mesoporous silica nanoparticles and gelatin nanoparticles
- Authors: Ngoepe, Mpho Phehello
- Date: 2019
- Subjects: Drug delivery systems , Pulmonary pharmacology , Nanosilicon , Nanomedicine , Nanoparticles , Mesoporous materials , Silica , Tuberculosis -- Treatment
- Language: English
- Type: text , Thesis , Doctoral , PhD
- Identifier: http://hdl.handle.net/10962/76519 , vital:30590
- Description: Pulmonary drug delivery has historically been used as a route for delivery of therapeutics for respiratory disease management. However, while there are many advantages, there are also some serious limitations, arising mostly from the physical aspects of the inhaler devices. This is more profound when the devices are the driving force for controlling particle size generation, which results in non-uniform particles that end up being swallowed/wasted/expelled. One promising solution to overcome this limitation is to pre-formulate nano/microscale particles with a high degree of manufacturing control. Nanomedicine has advanced such that there are already several nanoparticle formulations commercially available. In the case of tuberculosis treatment, there is an opportunity not only to examine the use of nanoparticles for inhalation therapy, but to take advantage of the fact that the physiochemical environment of diseased tissue is significantly different to health lung tissue (lower pH and increased enzyme concentrations). We formulated two series of nanoparticles, whose design included moieties that could respond to pH and enzymes. To address variability, a Box-Behnken statistical approach was followed to construct mesoporous silica nanoparticles. These “hard nanoparticles” can entrap both lipophilic and hydrophilic drugs and were coated with a pH-sensitive hydrazone linker. It was observed that pH, calcination temperature and ratio of water to silica source played the greatest role, not only in controlling the physicochemical properties of the nanoparticles but also the drug release rate. A second series of nanoparticles were synthesized based on gelatin. This was done partly to add support the comparison of hard (inorganic silica) versus soft, organic particles, but also to enable enzymatic degradation and drug release. Again, diseased lung tissue expresses increased concentrations of gelatinase enzymes that could be used to stimulate drug release at the site of the disease. In addition, it was observed that the non-ionic surfactant C12E10 could interact with the protein via hydrophobic interactions thus affecting the gelatin folding. The folding states affected crosslinking with the pH responsive linker, which in turn affected the rate of drug release. To support the synthetic work, we sought to develop a unique 3D lung model directly from MRI data of tuberculosis infected lungs. This would not only permit the evaluation of our nanoparticles but could be used as a proxy for in-vivo studies in future to predict lung deposition in diseased lung. Thus, this study shows that it is possible to synthesize pH and enzyme sensitive nanoparticles for pulmonary drug delivery in the treatment and management of pulmonary tuberculosis. These particles could be loaded with either hydrophobic or hydrophilic drugs and their distribution in the airway modelled using an in-silico 3D model based on real data. Further development and verification of these results should improve treatment for pulmonary diseases and conditions such as tuberculosis. This is especially urgent in the face of multi-drug resistance and poor side effects profiles for current treatment.
- Full Text:
- Date Issued: 2019
- Authors: Ngoepe, Mpho Phehello
- Date: 2019
- Subjects: Drug delivery systems , Pulmonary pharmacology , Nanosilicon , Nanomedicine , Nanoparticles , Mesoporous materials , Silica , Tuberculosis -- Treatment
- Language: English
- Type: text , Thesis , Doctoral , PhD
- Identifier: http://hdl.handle.net/10962/76519 , vital:30590
- Description: Pulmonary drug delivery has historically been used as a route for delivery of therapeutics for respiratory disease management. However, while there are many advantages, there are also some serious limitations, arising mostly from the physical aspects of the inhaler devices. This is more profound when the devices are the driving force for controlling particle size generation, which results in non-uniform particles that end up being swallowed/wasted/expelled. One promising solution to overcome this limitation is to pre-formulate nano/microscale particles with a high degree of manufacturing control. Nanomedicine has advanced such that there are already several nanoparticle formulations commercially available. In the case of tuberculosis treatment, there is an opportunity not only to examine the use of nanoparticles for inhalation therapy, but to take advantage of the fact that the physiochemical environment of diseased tissue is significantly different to health lung tissue (lower pH and increased enzyme concentrations). We formulated two series of nanoparticles, whose design included moieties that could respond to pH and enzymes. To address variability, a Box-Behnken statistical approach was followed to construct mesoporous silica nanoparticles. These “hard nanoparticles” can entrap both lipophilic and hydrophilic drugs and were coated with a pH-sensitive hydrazone linker. It was observed that pH, calcination temperature and ratio of water to silica source played the greatest role, not only in controlling the physicochemical properties of the nanoparticles but also the drug release rate. A second series of nanoparticles were synthesized based on gelatin. This was done partly to add support the comparison of hard (inorganic silica) versus soft, organic particles, but also to enable enzymatic degradation and drug release. Again, diseased lung tissue expresses increased concentrations of gelatinase enzymes that could be used to stimulate drug release at the site of the disease. In addition, it was observed that the non-ionic surfactant C12E10 could interact with the protein via hydrophobic interactions thus affecting the gelatin folding. The folding states affected crosslinking with the pH responsive linker, which in turn affected the rate of drug release. To support the synthetic work, we sought to develop a unique 3D lung model directly from MRI data of tuberculosis infected lungs. This would not only permit the evaluation of our nanoparticles but could be used as a proxy for in-vivo studies in future to predict lung deposition in diseased lung. Thus, this study shows that it is possible to synthesize pH and enzyme sensitive nanoparticles for pulmonary drug delivery in the treatment and management of pulmonary tuberculosis. These particles could be loaded with either hydrophobic or hydrophilic drugs and their distribution in the airway modelled using an in-silico 3D model based on real data. Further development and verification of these results should improve treatment for pulmonary diseases and conditions such as tuberculosis. This is especially urgent in the face of multi-drug resistance and poor side effects profiles for current treatment.
- Full Text:
- Date Issued: 2019
Formulation, development and assessment of efavirenz-loaded lipid nanocarriers
- Authors: Makoni, Pedzisai Anotida
- Date: 2014
- Subjects: Nanomedicine , Drug delivery systems , Antiretroviral agents Psychotropic effects , AIDS dementia complex
- Language: English
- Type: Master's theses , text
- Identifier: http://hdl.handle.net/10962/209981 , vital:47448
- Description: The feasibility of incorporating efavirenz (EFV) into innovative solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) using the hot high-pressure homogenization (HHPH) technique was investigated in an attempt to address the shortcomings in therapy associated with the use of conventional dosage forms. The shortcomings include the unpalatable taste of API in solution, instability in the presence of light when in solution and psychiatric side effects of the API. In particular, sustained release approaches may reduce or limit the incidence of adverse psychiatric effects of EFV and alleviate Acquired Immune Deficiency Syndrome (AIDS)-related complications such as AIDS Dementia Complex (ADC) in patients, ultimately improving their quality of life. Prior to initiating pre-formulation, formulation development and optimization studies of EFV-loaded SLN and/or NLC, Response Surface Methodology (RSM) in conjunction with central composite design (CCD), was used to develop and validate suitable methods for the quantitative determination of EFV in pharmaceutical formulations and for monitoring EFV release from SLN and/or NLC in vitro. Simple, accurate, precise, sensitive and stabilityindicating reversed phase-high performance liquid chromatography (RP-HPLC) methods with UV and electrochemical (EC) detection were developed, validated and optimized for in vitro analysis of EFV in formulations. On the basis of risk-to-benefit ratio the RP-HPLC method with UV detection was selected as the most suitable for the quantitative determination of EFV in pharmaceutical formulations, and was applied to in vitro release studies of EFV from SLN and/or NLC. Pre-formulation studies were undertaken to investigate the thermal stability of EFV so as to facilitate the selection of lipid excipients for the manufacture of nanocarriers, and to establish their compatibility with EFV. It was found that EFV was thermostable up to a temperature of approximately 200°C, indicating that HHPH could be used for the manufacture of EFV-loaded SLN and/or NLC. Lipid screening revealed that EFV is highly soluble in solid and liquid lipids, with glyceryl monostearate and Transcutol® HP showing the best solubilizing potential for EFV. Glyceryl monostearate exists in a stable β-modification prior to exposure to heat, but exists in the α-polymorphic modification following exposure to heat. It was established that the addition of Transcutol® HP to glyceryl monostearate revealed the co-existence of the α- and β’-polymorphic modifications, thereby revealing the existence of the modifications in NLC produced from the optimum lipid combination. Furthermore, an investigation of binary mixtures of EFV/glyceryl monostearate and glyceryl monostearate/Transcutol® HP, in addition to eutectic mixtures of EFV, glyceryl monostearate and Transcutol® HP, revealed no interaction between EFV and the lipids selected for the production of the nanocarriers. Due to the significantly higher solubility of EFV in Transcutol® HP than in to glyceryl monostearate, NLC are most likely to have a higher LC and EE than SLN. In addition, the existence of both the α- and β’-polymorphic modifications in the binary mixture of the lipid implies that EFV expulsion on prolonged storage is unlikely to occur from NLC when compared to SLN. Consequently formulation development and optimization studies of SLN and NLC were performed to investigate the potential to deliver EFV from a novel technology with an appropriate LC and EE for EFV. Tween®80 was selected for use in these formulations as the use of this surfactant facilitates the targeting of nanocarriers to the CNS. RSM in conjunction with a Box-Behnken Design (BBD) was used to establish the effects of process variables, such as number of homogenization cycles and pressure, in addition to formulation variables such as amount of EFV and Tween®80 on the particle size (PS), polydispersity index (PDI), zeta potential (ZP), visual assessment (VA) and release rate (RR) of EFV after 24 hours. In addition the LC and EE, degree of crystallinity and lipid modification, shape and surface morphology of the optimized batches were investigated to ensure that EFV-loaded SLN and NLC of desirable quality were produced. On the day of manufacture the mean PS and PDI of EFV-loaded SLN was 59.00 ± 23.16 nm and 0.382 ± 0.054 respectively. The mean PS and PDI of EFV-loaded NLC was 34.73 ± 0.7709 nm and 0.394 ± 0.027 respectively. The formulations were in the nanometer range and exhibited a narrow particle size distribution, as indicated by the PDI values. The ZP values for optimized SLN and NLC generated on the day of manufacture using HPLC grade water as the dispersion medium were -32.5 ± 4.99 mV and -22.4 ± 3.72 mV respectively. In addition the optimized batches of SLN and NLC revealed a decrease in crystallinity in comparison to bulk lipid material. DSC, WAXS and FT-IR revealed that EFV was molecularly dispersed in the nanocarriers. In addition EFV-loaded SLN existed in a single α-polymorphic form, whereas EFV-loaded NLC exhibited the co-existence of α- and β’-polymorphic forms. Generally SLN and NLC were spherically shaped when viewed under transmission electron microscopy (TEM) and scanning electron microscopy (SEM). On the day of manufacture the EE and LC of EFVloaded SLN was found to be 96.77 ± 0.453 % and 9.68 ± 1.772 % respectively. The EE and LC of EFV-loaded NLC was 99.93 ± 0.413 and 9.995 ± 0.672 respectively. The release profiles for the optimized formulations of SLN and NLC exhibited an initial burst release over the first 0-3 hours of testing, after which the release was sustained for up to 24 hours. The cumulative % EFV released over 24 hours was higher from SLN (91.5±3.423 %) than that observed for NLC (73.6±4.34 %). Stability studies performed for 8 weeks on the optimized batches of the SLN and the NLC were also conducted so as to ensure product quality. The formulations were assessed in terms of parameters considered benchmarks of stability, and included ZP, PS, PDI, LC and EE. Generally these parameters remained unchanged following storage for 8 weeks at 25°C/60% RH but showed considerable changes following storage for 8 weeks at 40°C/75% RH. These studies reveal that SLN and NLC when stored at 25°C/60% RH have the potential to be used as colloidal delivery systems for EFV that have the potential to protect EFV from photodegradation and sustain release into brain tissue. The latter will ultimately reduce or limit the incidence of adverse psychiatric effects and potentially alleviate AIDS-related complications such as ADC in patients with HIV/AIDS, ultimately improving their quality of life. , Thesis (MSc) -- Faculty of Pharmacy, Pharmacy, 2014
- Full Text:
- Date Issued: 2014
- Authors: Makoni, Pedzisai Anotida
- Date: 2014
- Subjects: Nanomedicine , Drug delivery systems , Antiretroviral agents Psychotropic effects , AIDS dementia complex
- Language: English
- Type: Master's theses , text
- Identifier: http://hdl.handle.net/10962/209981 , vital:47448
- Description: The feasibility of incorporating efavirenz (EFV) into innovative solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) using the hot high-pressure homogenization (HHPH) technique was investigated in an attempt to address the shortcomings in therapy associated with the use of conventional dosage forms. The shortcomings include the unpalatable taste of API in solution, instability in the presence of light when in solution and psychiatric side effects of the API. In particular, sustained release approaches may reduce or limit the incidence of adverse psychiatric effects of EFV and alleviate Acquired Immune Deficiency Syndrome (AIDS)-related complications such as AIDS Dementia Complex (ADC) in patients, ultimately improving their quality of life. Prior to initiating pre-formulation, formulation development and optimization studies of EFV-loaded SLN and/or NLC, Response Surface Methodology (RSM) in conjunction with central composite design (CCD), was used to develop and validate suitable methods for the quantitative determination of EFV in pharmaceutical formulations and for monitoring EFV release from SLN and/or NLC in vitro. Simple, accurate, precise, sensitive and stabilityindicating reversed phase-high performance liquid chromatography (RP-HPLC) methods with UV and electrochemical (EC) detection were developed, validated and optimized for in vitro analysis of EFV in formulations. On the basis of risk-to-benefit ratio the RP-HPLC method with UV detection was selected as the most suitable for the quantitative determination of EFV in pharmaceutical formulations, and was applied to in vitro release studies of EFV from SLN and/or NLC. Pre-formulation studies were undertaken to investigate the thermal stability of EFV so as to facilitate the selection of lipid excipients for the manufacture of nanocarriers, and to establish their compatibility with EFV. It was found that EFV was thermostable up to a temperature of approximately 200°C, indicating that HHPH could be used for the manufacture of EFV-loaded SLN and/or NLC. Lipid screening revealed that EFV is highly soluble in solid and liquid lipids, with glyceryl monostearate and Transcutol® HP showing the best solubilizing potential for EFV. Glyceryl monostearate exists in a stable β-modification prior to exposure to heat, but exists in the α-polymorphic modification following exposure to heat. It was established that the addition of Transcutol® HP to glyceryl monostearate revealed the co-existence of the α- and β’-polymorphic modifications, thereby revealing the existence of the modifications in NLC produced from the optimum lipid combination. Furthermore, an investigation of binary mixtures of EFV/glyceryl monostearate and glyceryl monostearate/Transcutol® HP, in addition to eutectic mixtures of EFV, glyceryl monostearate and Transcutol® HP, revealed no interaction between EFV and the lipids selected for the production of the nanocarriers. Due to the significantly higher solubility of EFV in Transcutol® HP than in to glyceryl monostearate, NLC are most likely to have a higher LC and EE than SLN. In addition, the existence of both the α- and β’-polymorphic modifications in the binary mixture of the lipid implies that EFV expulsion on prolonged storage is unlikely to occur from NLC when compared to SLN. Consequently formulation development and optimization studies of SLN and NLC were performed to investigate the potential to deliver EFV from a novel technology with an appropriate LC and EE for EFV. Tween®80 was selected for use in these formulations as the use of this surfactant facilitates the targeting of nanocarriers to the CNS. RSM in conjunction with a Box-Behnken Design (BBD) was used to establish the effects of process variables, such as number of homogenization cycles and pressure, in addition to formulation variables such as amount of EFV and Tween®80 on the particle size (PS), polydispersity index (PDI), zeta potential (ZP), visual assessment (VA) and release rate (RR) of EFV after 24 hours. In addition the LC and EE, degree of crystallinity and lipid modification, shape and surface morphology of the optimized batches were investigated to ensure that EFV-loaded SLN and NLC of desirable quality were produced. On the day of manufacture the mean PS and PDI of EFV-loaded SLN was 59.00 ± 23.16 nm and 0.382 ± 0.054 respectively. The mean PS and PDI of EFV-loaded NLC was 34.73 ± 0.7709 nm and 0.394 ± 0.027 respectively. The formulations were in the nanometer range and exhibited a narrow particle size distribution, as indicated by the PDI values. The ZP values for optimized SLN and NLC generated on the day of manufacture using HPLC grade water as the dispersion medium were -32.5 ± 4.99 mV and -22.4 ± 3.72 mV respectively. In addition the optimized batches of SLN and NLC revealed a decrease in crystallinity in comparison to bulk lipid material. DSC, WAXS and FT-IR revealed that EFV was molecularly dispersed in the nanocarriers. In addition EFV-loaded SLN existed in a single α-polymorphic form, whereas EFV-loaded NLC exhibited the co-existence of α- and β’-polymorphic forms. Generally SLN and NLC were spherically shaped when viewed under transmission electron microscopy (TEM) and scanning electron microscopy (SEM). On the day of manufacture the EE and LC of EFVloaded SLN was found to be 96.77 ± 0.453 % and 9.68 ± 1.772 % respectively. The EE and LC of EFV-loaded NLC was 99.93 ± 0.413 and 9.995 ± 0.672 respectively. The release profiles for the optimized formulations of SLN and NLC exhibited an initial burst release over the first 0-3 hours of testing, after which the release was sustained for up to 24 hours. The cumulative % EFV released over 24 hours was higher from SLN (91.5±3.423 %) than that observed for NLC (73.6±4.34 %). Stability studies performed for 8 weeks on the optimized batches of the SLN and the NLC were also conducted so as to ensure product quality. The formulations were assessed in terms of parameters considered benchmarks of stability, and included ZP, PS, PDI, LC and EE. Generally these parameters remained unchanged following storage for 8 weeks at 25°C/60% RH but showed considerable changes following storage for 8 weeks at 40°C/75% RH. These studies reveal that SLN and NLC when stored at 25°C/60% RH have the potential to be used as colloidal delivery systems for EFV that have the potential to protect EFV from photodegradation and sustain release into brain tissue. The latter will ultimately reduce or limit the incidence of adverse psychiatric effects and potentially alleviate AIDS-related complications such as ADC in patients with HIV/AIDS, ultimately improving their quality of life. , Thesis (MSc) -- Faculty of Pharmacy, Pharmacy, 2014
- Full Text:
- Date Issued: 2014
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